tbuckley/cabot-search huggingface dataset:
Abstract LB353: The switch from cap-dependent to cap-independent translation reshapes the immunopeptidome of lung cancer
Authors: Anika N. Ali, Andrew D. Weeden, Alex M. Jaeger
Journal: Cancer Research (2023)

Abstract Cancer immunosurveillance relies on the presentation of peptide antigens on human leuckocyte antigen class I (HLA-I). HLA-I molecules present a diverse array of antigens, known as the “immunopeptidome”, which are recognized by cytotoxic CD8+ T cells. Recent evidence suggests that cryptic peptide antigens derived from non-canonical open reading frames (nuORFs) contribute to the immunopeptidome and drive CD8+ T cell responses. Integrating ribosome profiling (Ribo-seq) with mass spectrometry (MS) analyses has enabled the identification of several cryptic peptides derived from nuORFs including from putative non-coding regions including the 5’UTR, 3’UTR, long non coding RNAs (lncRNAs) and retained introns. Notably, many nuORFs undergo cap-independent translation. Various physiological and pharmacological stressors arrest canonical cap-dependent translation initiation and induce cap-independent translation. However, how this shift in translational dynamics influences the immunopeptidome is unknown. Using lung cancer cell lines, we show that the eIF4A inhibitor silvestrol induces cap-independent translation and reshapes the landscape of nuORF-derived peptide antigens. Silvestrol induced changes in the immunopeptidome strongly contrast with the global translation inhibitor homoharringtonine, which dampens antigen presentation. These observations suggest that the presentation of nuORF antigens in lung cancer is dynamic and tightly controlled by translational dynamics. More broadly, our study provokes reconsideration of translation inhibitors as immunomodulatory drugs that can change the HLA-I antigen repertoire and generate peptides that can act as new targets for cancer immunotherapy. Citation Format: Anika N. Ali, Andrew D. Weeden, Alex M. Jaeger. The switch from cap-dependent to cap-independent translation reshapes the immunopeptidome of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB353.
Abstract LB092: Identification of target antigens for logic-gated CAR-T therapeutics for the treatment of clear cell renal cell carcinoma: conditional targeting of CA9 with a PSMA PrimeR
Authors: Nickolas Attanasio, Levi Gray-Rupp, Stanley Zhou, Samuel A. Williams
Journal: Cancer Research (2023)

Abstract Chimeric antigen receptor T (CAR T) cell therapeutics have produced curative outcomes in hematological malignancies but have yet to be developed into safe and effective therapies for solid tumors. A major obstacle to developing targeted therapies against solid malignancies is the identification of targets that are abundantly and broadly expressed on tumor cells while exhibiting an absence of expression on high toxicity risk normal tissues. Logic-gated CAR T cells that inducibly express CAR upon recognition of a target antigen by a secondary engineered priming receptor (PrimeR) offer a novel approach to permit conditional killing activity in the presence of two antigens. Here, we identify PSMA and CA9 as attractive priming and cytolytic antigen targets, respectively, in clear cell renal cell carcinoma (ccRCC). Using a bioinformatic discovery path, we show PSMA and CA9 mRNA are co-expressed in 94% of ccRCC tumors (n=530, TCGA). Immunohistochemical (IHC) assessments further reveal robust membranous PSMA and CA9 protein coexpression in 80% of ccRCC (n=416). Expression of CA9 and PSMA was evaluated across disease stage and co-expression was confirmed throughout disease progression. Distant metastases similarly showed evidence of common expression. In contrast, IHC assessment of normal tissues revealed limited membranous coexpression of PSMA and CA9 in normal high-risk toxicity tissues. These findings collectively support the utility of PSMA and CA9 as target antigens for AND-logic-gated therapeutics for the treatment of ccRCC. Citation Format: Nickolas Attanasio, Levi Gray-Rupp, Stanley Zhou, Samuel A. Williams. Identification of target antigens for logic-gated CAR-T therapeutics for the treatment of clear cell renal cell carcinoma: conditional targeting of CA9 with a PSMA PrimeR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB092.
Abstract LB119: Recurrence score for recurrence over survival outcome in the landmark TAILORx trial
Authors: Sherry X. Yang, John Yu, Molin Wang
Journal: Cancer Research (2023)

Abstract Overall survival is the most relevant endpoint in clinical research and patient care. Nonetheless, cancer recurrence has been frequently utilized as a surrogate endpoint, particularly in the context of multi-gene assays and molecular signatures. The 21-gene recurrence score (RS) was originally established against distant recurrence for prognosis in breast cancer. However, it is unclear whether RS has a weight for the recurrence over survival prognosis. We investigated RS on the choice of clinical endpoints in the Trial Assigning Individualized Options for Treatment (TAILORx), which had OS, invasive disease-free survival (DFS), and recurrence-free interval (RFI) in addition to distant recurrence-free interval as the clinical endpoints. Both midrange (11-25) and high-range (26-100) scores were associated with RFI, high-range only with DFS, but not significantly associated with OS in the multivariable Cox proportional-hazards regression models. Of 462 death events, 33.1% (153 events) were ascribed to breast cancer and 91.8% (424) were due to DFS-related events that included 24.5% other cancers, 34.2% unknown and 33.1% breast cancer. It is DFS that was wound up as the most representative surrogate endpoint for survival. The lack of survival significance was probably due to the nature of 21-gene assay weighted for recurrence rather than not having enough event numbers in the TAILORx clinical trial. The data call for establishing biomarkers directly towards OS or DFS to increase survival with more precision. Citation Format: Sherry X. Yang, John Yu, Molin Wang. Recurrence score for recurrence over survival outcome in the landmark TAILORx trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB119.
Abstract LB157: Cereblon inhibits prostate cancer progression and metastasis by negatively regulating 6PGD
Authors: Koushik Guchhait, Hyeon Seung Yoon, Seungheon Shin, Hyun-Su An, Hye Seung Nam, Francisco D. Yanqui-Rivera, Samara M. Oña, Miguel Á. Mendez, Seokjae Park, Eun-Kyoung Kim, Jong Yeon Hwang, Jee-Young Han, Doo Yong Chung, Daeho Park, Su-Geun Yang, Chul-Seung Park, Steve K. Cho
Journal: Cancer Research (2023)

Abstract As the third enzyme of the pentose phosphate pathway (PPP), abnormally elevated levels of 6-phosphogluconate dehydrogenase (6PGD) have been documented in various human cancers. We demonstrate that reduced cereblon (CRBN) protein expression is the underlying mechanism of elevated 6PGD expression in metastatic prostate cancer cells. We establish 6PGD as a new endogenous substrate for CRBN by demonstrating that it interacts directly with CRBN and is ubiquitinated by CRL4CRBN. In addition, CRBN negatively regulates prostate cancer cell progression and metastasis, as abnormally high 6PGD, in the absence of sufficient CRBN, enhances the metastatic potential of prostate cancer in vitro and in vivo. Our findings show convincingly that carbohydrate metabolism regulated by 6PGD is linked to prostate cancer metastasis via CRBN. Based on these data, we propose that the 6PGD-CRBN axis may be a suitable target for further research into new therapeutics for mitigating prostate cancer metastasis. Citation Format: Koushik Guchhait, Hyeon Seung Yoon, Seungheon Shin, Hyun-Su An, Hye Seung Nam, Francisco D. Yanqui-Rivera, Samara M. Oña, Miguel Á. Mendez, Seokjae Park, Eun-Kyoung Kim, Jong Yeon Hwang, Jee-Young Han, Doo Yong Chung, Daeho Park, Su-Geun Yang, Chul-Seung Park, Steve K. Cho. Cereblon inhibits prostate cancer progression and metastasis by negatively regulating 6PGD [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB157.
Abstract LB049: ALKBH5 emerges as a novel regulator of the BCR pathway
Authors: Bandish B. Kapadia, Anirban Roychowdhury, Forum Kayastha, Nahid Nanaji, Jolene Windle, Ronald B. Gartenhaus
Journal: Cancer Research (2023)

Abstract Global epitranscriptomic methylation of mRNA at the N6 position (m6A) is reported to be altered in B-cell and tumor development. However, the mechanistic underpinnings of its role in the pathogenesis of Diffuse large B cell lymphoma (DLBCL) are unknown. It is well established that the B-cell receptor (BCR) pathway is a primary oncogenic driver in aggressive B-cell lymphomas. We previously reported that the Ataxia Telangiectasia Mutated (ATM)/Hu Antigen R (HuR)axis, as well as Eukaryotic Translation Initiation Factor 4A (eIF4A), modulate BCR signaling. However, the impact of RNA modifications on BCR induction is still poorly understood. Addressing this burgeoning question, we noted enhanced expression of AlkB Homolog 5 (ALKBH5), an m6A demethylase, in naïve B-cells treated with BCR mimetics. Similarly, mRNA levels of ALKBH5 were reported to be modestly enhanced in IgM-treated human B-cells (GSE156195). Consistently, immunization of C57BL/6 mice with sheep red blood cells (SRBC) significantly enhanced ALKBH5 in splenic B-cells. Next, evaluating the impact of BCR induction in lymphomagenesis, we observed a robust increase in the demethylase expression in BCR mimetic-treated DLBCL cells. Notably, increased expression of ALKBH5 was observed in a murine EµMyc model and primary DLBCL tumors. In coherence, the enhanced transcript levels of ALKBH5 in TCGA-DLBCL have prognostic implications. To gain functional insight, we depleted ALKBH5, which resulted in a robust reduction of BCR pathway proteins. Unexpectedly, the mRNA levels of CD79a and BLK were minimally modified, while the SYK, BTK, and CARD11 messages were reduced. Further studies are ongoing to evaluate the potential mechanism of mRNA transport and/or stability. Citation Format: Bandish B. Kapadia, Anirban Roychowdhury, Forum Kayastha, Nahid Nanaji, Jolene Windle, Ronald B. Gartenhaus. ALKBH5 emerges as a novel regulator of the BCR pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB049.
Abstract LB154: Circ0003039 interacts with calreticulin to inhibit the progression of hepatocellular carcinoma by suppressing wnt/beta-catenin signaling pathway
Authors: Yue-Ning Wang, Yu-Feng Zhou, Ji Liu, Mei-Yin Zhang, Shuo-Cheng Wang, Shi-Juan Mai, Hui-Yun Wang
Journal: Cancer Research (2023)

Abstract Background: Circular RNAs (circRNAs) are covalently closed and single-stranded RNAs which play critical roles in various biological processes and diseases including cancers. The functions and mechanisms of circRNAs in hepatocellular carcinoma (HCC) are still need to be clarified. Methods: Custom circRNA microarray was performed to investigate the profile of circRNAs in HCC. Expression of circ0003039 and its clinical significance in 60 pairs of HCC and matched non-cancer liver tissues were identified and confirmed by microarray and quantitative RT-PCR. The biological functions of circ0003039 were investigated by gain-and loss-of-function experiments in vitro and in vivo. RNA pull-down, mass spectrometry, RNA-immunoprecipitation, Co-immunoprecipitation, fluorescent in situ hybridization were used to identify circ0003039-protein interaction. The downstream pathway regulated by circ0003039 was explored using RNA-seq and verified using western blot and immunofluorescence. Results: Expression of circ0003039 was reduced in HCC tissues and positively associated with the overall survival of HCC patients. Circ0003039 was located in cytoplasm of HCC cells. Ectopic overexpression of circ0003039 inhibited the proliferation, colony formation, migration and invasion of HCC cells and the growth of HCC xenograft in mice, while knockdown of circ0003039 had opposite effects in HCC cells. Mechanistically, circ0003039 bound to the N-terminal domain of CALR protein and acted as a scaffold to enhance the interaction of CALR with CAPN2, which promoted the degradation of CALR protein by the enzymatic activity of CAPN2. Rescue experiments showed that circ0003039 inhibited HCC proliferation via suppressing CALR protein. Finally, we found that circ0003039 inhibited HCC cells by suppressing CALR-mediated wnt-βcatenin signaling pathway. Conclusions: Our study demonstrates that circ0003039 bind to N-terminal domain of CALR and facilitated CAPN2 to degrade CALR protein, which inhibits the development and progression of HCC via suppressing CALR-mediated wnt-βcatenin signaling pathway, and circ0003039 is a potential prognostic biomarker and therapeutic target for HCC. Citation Format: Yue-Ning Wang, Yu-Feng Zhou, Ji Liu, Mei-Yin Zhang, Shuo-Cheng Wang, Shi-Juan Mai, Hui-Yun Wang. Circ0003039 interacts with calreticulin to inhibit the progression of hepatocellular carcinoma by suppressing wnt/beta-catenin signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB154.
Abstract LB153: Inhibiting BRD4 as a proposed alternative therapeutic strategy for HPV16-associated head and neck squamous cell carcinoma
Authors: Dhruthi Suresh, Chitrasen Mohanty, Albert R. Wang, Christina Kendziorski, Gopal Iyer
Journal: Cancer Research (2023)

Abstract Integration of Human Papilloma Virus (HPV) 16 into human genomes is an integral event for cancer progression in Head and Neck Squamous Cell Carcinoma (HNSCC). There is a need to differentiate treatment for HPV-16 integrated HNSCC from other subtypes. We hypothesize that by inhibiting Bromodomain Extra Terminal (BET) protein BRD4, a transcriptional co-regulator of host and viral genes can advance treatment in patients with the integrated subtype of HPV16 associated HNSCC. Through small molecule inhibition and knockdown of BRD4 in seven model HPV-16 integrated cell lines, we demonstrated that BRD4 down-regulates the expression of viral genes E6, E7, independent of viral E2 type of integration. Given that E6 expression is mediated by BRD4, E6-p53 interactions was abrogated as revealed through increased expression of p53. Furthermore, BRD4 inhibition caused downregulation of c-Myc. This result also suggests the function of BRD4 in the regulation of proteins in cell cycle regulation, including E2F1 and p21. BRD4 inhibition was also shown to delay DNA damage response (DDR) by reducing the expression of RAD51 in 6 out of 7 cell lines. RNA-sequencing results give further insight regarding the downregulation of genes involved in DDR – RAD51, BRCA1 and BRCA2 in all cell lines. RNA-sequencing data also gives us an understanding of the implication of BRD4-inhibition in other genes involved in cell cycle regulation. Knockdown of BRD4 done through small hairpin RNA (shRNA) constructs phenocopied the effects shown through inhibition of BRD4. Additionally, treating the above-mentioned cell lines with BRD4 inhibitor (JQ1) followed by radiation showed further downregulation of viral oncogenes E6, and E7. This suggests that combining radiation and JQ1 treatment can be a viable combination treatment. De-escalating radiation treatment with BRD4 inhibition has potential to be an effective combination treatment for HPV16 integrated HNSCC. Citation Format: Dhruthi Suresh, Chitrasen Mohanty, Albert R. Wang, Christina Kendziorski, Gopal Iyer. Inhibiting BRD4 as a proposed alternative therapeutic strategy for HPV16-associated head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB153.
Abstract LB074: Towards the next generation cancer dependency map
Authors: Kirsty Wienand, Samantha Stokes, Philip G. Montgomery, Kelly Sullivan, Joshua M. Dempster, William C. Hahn, Jennifer A. Roth, Francisca Vazquez
Journal: Cancer Research (2023)

Abstract Cancer genome alterations that cause cancer cells to grow also confer vulnerabilities, which normal cells lack. The challenge is that, for the majority of cancers, we do not understand the relationship between the genetic alterations and the dependencies they cause. To solve this problem, we are creating a Cancer Dependency Map (DepMap) by systematically identifying genetic dependencies and small molecule sensitivities as well as discovering the biomarkers that predict them. Since its inception, DepMap has compiled data for over eighteen hundred cell line models, performed more than a thousand CRISPR screens, and drug sensitivity profiles using PRISM in over 500 cell lines as well as developed new analytic methods for the identification of cancer vulnerabilities. DepMap is being used by researchers around the world and numerous potential therapeutic targets have been identified using this resource. However, we are still in the early stages of having a complete map and we will discuss our ongoing work towards making the Cancer Dependency Map more powerful. The next generation DepMap will include more complex cellular models including 3D models, representing pediatric and rare cancers, and expanding the perturbation space to include combinations. Additionally, we are performing novel types of omics characterization and building new computational and visualizations tools. These new scientific directions will help make progress towards our identification of the landscape of cancer vulnerabilities and create a roadmap for cancer therapeutics. Citation Format: Kirsty Wienand, Samantha Stokes, Philip G. Montgomery, Kelly Sullivan, Joshua M. Dempster, William C. Hahn, Jennifer A. Roth, Francisca Vazquez. Towards the next generation cancer dependency map [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB074.
Abstract LB253: Long-read single-cell sequencing of liver cancer
Authors: Jian-Hua Luo, Silvia Liu, Bao-Guo Ren, Yan-Ping Yu
Journal: Cancer Research (2023)

Abstract The protein diversity of mammalian cells is determined by arrays of isoforms from genes. Protein mutation is essential in species evolution and cancer development. Accurate Long-read transcriptome sequencing at single-cell level is required to decipher the spectrum of protein expressions in mammalian organisms. In this report, we developed a synthetic long-read single-cell sequencing technology based on LOOPseq technique. We applied this technology to analyze 447 transcriptomes of hepatocellular carcinoma (HCC) and benign liver from an individual. Through Uniform Manifold Approximation and Projection (UMAP) analysis, we identified a panel of mutation mRNA isoforms highly specific to HCC cells. The evolution pathways that led to the hyper-mutation clusters in single human leukocyte antigen (HLA) molecules were identified. Novel fusion transcripts were detected. The combination of gene expressions, fusion gene transcripts, and mutation gene expressions significantly improved the classification of liver cancer cells versus benign hepatocytes. In conclusion, LOOPseq single-cell technology may hold promise to provide a new level of precision analysis on the mammalian transcriptome. Citation Format: Jian-Hua Luo, Silvia Liu, Bao-Guo Ren, Yan-Ping Yu. Long-read single-cell sequencing of liver cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB253.
Abstract LB082: The CytoR1: a standardized dielectrophoretic platform for label free sorting
Authors: Dean E. Thomas, Katherine E. Degen, Ridi Barua, Andrea Bertke, Erin A. Henslee, Alexandra R. Hyler
Journal: Cancer Research (2023)

Abstract Dielectrophoresis (DEP), a label-free electrokinetic technique, has a long history of being used to characterize and separate target subpopulations from mixed samples. A large body of literature has investigated these parameters with unique setups and limited cell varieties. The technical challenge of the technique coupled with the uncertainty in the breadth of data has limited the commercialization and widespread adoption of DEP for biological applications. The work presented here aims to evaluate a range of prior applications of DEP on a standardized platform. A variety of cell types were characterized and compared to literature values considering variables such as frequency, voltage, and flow rate. Once a cell type’s frequency response curve is generated, it is possible to design workflows to enrich that cell type from a bulk mixture, without antibody labeling. Here, we test various cell types and characteristics on a microfluidics-based, benchtop cell sorting technology, the CytoR1. First, the CytoR1 successfully facilitated the separation of ovarian cancer stem cells (CSCs) from peripheral blood mononuclear cells (PBMCs), both from mice. From a 56.2% CSCs and 43.8% PMBCs co-culture, we were able to deplete 50% of the PMBCs while retaining the original CSC population. Further work investigated the ability to sort neuron subpopulations. Live neurons can be isolated from a bulk preparation and further enriched by size and phenotype with varying voltage and frequency settings. By modulating voltage and flow rate in addition to frequency, a distinct population of small neurons can be isolated for further study. Finally, cell state can be investigated. Red blood cells were characterized in both their native and oxidatively stressed states. Curves show a distinct shift towards higher frequencies with increasing oxidative stress suggesting the ability to separate these populations from each other. Together these data suggest the versatility of a robust, DEP-based sorting platform, the CytoR1, for label free cell sorting. Citation Format: Dean E. Thomas, Katherine E. Degen, Ridi Barua, Andrea Bertke, Erin A. Henslee, Alexandra R. Hyler. The CytoR1: a standardized dielectrophoretic platform for label free sorting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB082.
Author Correction: The stress kinase MKK7 couples oncogenic stress to p53 stability and tumor suppression
Authors: Daniel Schramek, Athanassios Kotsinas, Arabella Meixner, Teiji Wada, Ulrich Elling, J. Andrew Pospisilik, G. Gregory Neely, Ralf-Harun Zwick, Verena Sigl, Guido Forni, Manuel Serrano, Vassilis G. Gorgoulis, Josef M. Penninger
Journal: Nature Genetics (2023)